- PURPOSE: This study addressed the efficacy and toxicity of the novel compound Bryostatin-1 (NSC 339555), a novel agent with antineoplastic, hematopoietic and immunomodulatory activity in a variety of in vitro and in vivo systems. PATIENTS AND METHODS: This phase II study randomly assigned chemotherapy-naïve patients with untreated metastatic melanoma and measurable disease to two schedules of treatment: Arm A, 25 microg/m2 bryostatin-1 given as a 24 hour continuous infusion weekly or Arm B, 120 microg/m2 bryostatin-1 given as a 72 hour continuous infusion every 2 weeks. Although objective response was assessed using standard NCIC CTG criteria, antitumour activity was assessed using a multivariate endpoint incorporating both response (CR and PR) and early progression (PD at < or = 8 weeks). Seventeen patients were randomized to each arm. RESULTS: Arm A was better tolerated with 86.7% of 15 evaluable patients receiving > or = 90% of planned dose intensity versus 76.5% of 17 evaluable patients in Arm B. On Arm B, three patients experienced serious adverse events and three patients had to be removed from protocol therapy due to toxicity. The most common side effect was myalgia (33% grade 1-2 on Arm A versus 65% on Arm B with 5 patients experiencing grade 3 and one patient grade 4). Lethargy was more common on Arm A but more severe on Arm B. Other side effects such as nausea, diarrhea and headache were generally mild to moderate in nature and occurred with a similar frequency on both arms. Hematologic and biochemical toxicity were minimal. This trial was closed early because the protocol-stopping rule was met based on lack of required responses and on the number of early progressions on both arms. No partial or complete responses were seen; 3 patients randomized to Arm A had stable disease (duration 9-24 weeks) as did 4 patients (duration 10-38 weeks) randomized to Arm B. CONCLUSION: Arm A was better tolerated than Arm B. We conclude that bryostatin-1 has little efficacy in the treatment of metastatic melanoma with either of the schedules studied.